Variant chr18-42004523-G-T details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PP3_ModerateBS2

The NM_002647.4(PIK3C3):c.1152G>T(p.Leu384Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000201 in 1,440,672 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Synonymous variant affecting the same amino acid position (i.e. L384L) has been classified as Benign.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.000020 ( 0 hom. )

Consequence

PIK3C3
NM_002647.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.14

Variant links:

Genes affected

PIK3C3 (HGNC:8974): (phosphatidylinositol 3-kinase catalytic subunit type 3) Enables 1-phosphatidylinositol-3-kinase activity. Involved in early endosome to late endosome transport and regulation of cytokinesis. Acts upstream of or within autophagy and protein lipidation. Located in autolysosome; late endosome; and midbody. [provided by Alliance of Genome Resources, Apr 2022]

PIK3C3 links:

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ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -2 ACMG points.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.897

BS2

High AC in GnomAdExome4 at 29 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PIK3C3	NM_002647.4 linkuse as main transcript	c.1152G>T	p.Leu384Phe	missense_variant	10/25	ENST00000262039.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PIK3C3	ENST00000262039.9 linkuse as main transcript	c.1152G>T	p.Leu384Phe	missense_variant	10/25	1	NM_002647.4	P1
PIK3C3	ENST00000398870.7 linkuse as main transcript	c.963G>T	p.Leu321Phe	missense_variant	9/24	2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.0000201

AC:

AN:

1440672

Hom.:

Cov.:

AF XY:

0.0000168

AC XY:

AN XY:

716164

show subpopulations

Gnomad4 AFR exome

AF:

0.0000312

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000253

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Mar 02, 2023

The c.1152G>T (p.L384F) alteration is located in exon 10 (coding exon 10) of the PIK3C3 gene. This alteration results from a G to T substitution at nucleotide position 1152, causing the leucine (L) at amino acid position 384 to be replaced by a phenylalanine (F). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.99

BayesDel_addAF

Pathogenic

0.36

BayesDel_noAF

Pathogenic

0.27

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.98

D;.;D

Eigen

Uncertain

0.32

Eigen_PC

Benign

0.17

FATHMM_MKL

Uncertain

0.87

LIST_S2

Pathogenic

1.0

D;D;D

M_CAP

Uncertain

0.23

MetaRNN

Pathogenic

0.90

D;D;D

MetaSVM

Uncertain

-0.030

MutationAssessor

Pathogenic

3.7

H;.;.

MutationTaster

Benign

1.0

D;D

PrimateAI

Pathogenic

0.81

PROVEAN

Uncertain

-3.8

D;.;D

REVEL

Uncertain

0.63

Sift

Uncertain

0.0030

D;.;D

Sift4G

Uncertain

0.0040

D;.;D

Polyphen

1.0

D;.;D

Vest4

0.82

MutPred

0.81

Gain of catalytic residue at R385 (P = 0.1696);Gain of catalytic residue at R385 (P = 0.1696);.;

MVP

0.81

MPC

0.81

ClinPred

1.0

GERP RS

1.5

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.63

gMVP

0.65

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

No publications associated with this variant yet.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over